Dasatinib and quercetin mitigate radiation-induced lung injury by eliminating senescent cells in a rat model

TL;DR

Dasatinib and quercetin reduce radiation-induced lung injury in rats by targeting and eliminating senescent cells.

Contribution

This study demonstrates that dasatinib and quercetin mitigate radiation-induced lung injury by reducing senescent cell burden and suppressing inflammatory responses.

Findings

DQ treatment reduced inflammatory cell infiltration and collagen deposition in irradiated lungs.

DQ decreased senescence markers and SASP factors while activating apoptotic pathways.

Transcriptomic analysis linked DQ effects to p53, MAPK, PI3K-Akt, and mitophagy signaling modulation.

Abstract

Radiation-induced lung injury (RILI) is a major dose-limiting toxicity in thoracic radiotherapy, and accumulating evidence implicates radiation-induced cellular senescence in its pathogenesis. This study aimed to investigate whether combination therapy with dasatinib and quercetin (DQ) could mitigate RILI by reducing senescent cell burden.

A rat model of RILI was established using a single 30 Gy irradiation to the right lung. Pulmonary pathological changes, fibrosis, DNA damage, and cellular senescence were assessed by histology, immunofluorescence, senescence-associated β-galactosidase staining, Western blotting and immunohistochemistry. Transcriptomic profiling was performed to explore the underlying molecular mechanisms.

Compared with irradiation alone, DQ treatment significantly alleviated radiation-induced inflammatory cell infiltration and collagen deposition, reduced γH2AX levels, decreased senescence-associated markers p53, p21, and p16, and suppressed multiple senescence-associated secretory phenotype (SASP) factors. Transcriptomic analysis indicated that DQ-mediated effects were closely associated with activation of apoptotic pathways and modulation of p53, MAPK, PI3K-Akt and mitophagy signaling cascades.

DQ attenuated RILI in rats, with effects consistent with the reduced radiation-induced senescent cells and suppression of senescence-associated inflammatory responses.

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